Means for creating a mass having structural integrity

ABSTRACT

The present invention relates to a means for creating a mass having structural integrity, including a rapidly disintegratable tablet for administration with or without the use of water. The present invention has a wide variety of different uses and applications. One embodiment is a tablet intended for oral administration. The tablet comprises at least one active ingredient and a mixture of excipients. The excipients provide desired characteristics and physical properties and when the tablet is sintered or heated, excellent tablet binding characteristics are obtained. The tablet is intended primarily for oral administration and dissolves in the presence of water. Also disclosed is a process for the preparation of a rapidly disintegratable tablet for administration with or without the use of water. The process comprising dissolving at least one bulking agent and at least one structural agent in a suitable solvent, wherein the solvent provides high porosity upon drying; spray-drying or dispersing said dissolved mixture to obtain a bead or granulated product; dry blending at least one binding agent, and at least one active ingredient with the bead or granulated product to obtain a preformulation product or adding at least one active ingredient to the preformulation product dissolved or dispersed components before spray-drying or dispersing; compressing the preformulation product; and sintering or heating the preformulation product for a sufficient time and temperature to allow the binding agent to change status or melt and allow the binding agent to resolidify as the temperature is reduced to ambient temperature.

This application is a continuation application of U.S. patentapplication Ser. No. 09/366,686, filed Aug. 4, 1999 now U.S. Pat. No.6,284,270, the entire contents of which are hereby incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to a quick dissolving or disintegratingsolid product or dosage form intended for a wide variety of uses,including oral administration to a patient to achieve a desiredtherapeutic response.

BACKGROUND OF THE INVENTION

Patient compliance remains a significant problem in health care.Compliance is dependent on a number of factors including but not limitedto the route and frequency of drug administration. Frequency ofadministration can sometimes be decreased by administering long-acting,sustained release, or controlled release pharmaceutical formulations.These techniques have been of tremendous benefit, especially for oraladministration. However, oral dosage forms themselves oftentimes haveserious disadvantages that adversely affect patient compliance.

Oral dosage forms remain a significant problem for a significant segmentof the population. Many patients are unable or unwilling to swallow asolid dosage form. This problem occurs primarily in children and theelderly, however, problems with swallowing are not limited to thosesegments of the population. Certain conditions or disease statesmanifest themselves by swallowing difficulties. Otherwise healthyindividuals can also exhibit problems with swallowing. Such swallowingdifficulties irrespective of their cause can severely compromise patientcompliance. In addition, swallowing difficulties are not limited tohumans and swallowing remains a significant issue in medicating animals.

The pharmaceutical industry has long-recognized the need for a form oforal administration which avoids the swallowing difficulties associatedwith a traditional tablet. Syrups, elixirs, microcapsules containingslurries, chewable tablets and other novel tablet or capsule dosageforms have been developed. None of these dosage forms have been idealand each has their own disadvantages. The disadvantages include a morecostly process for preparation and/or more costly packaging materials.

A number of researchers have described a wide variety of techniques forobviating or minimizing swallowing problems. Aikire et al, U.S. Pat. No.5,607,697 discloses an oral dosage form which is composed of a pluralityof microparticles each having a core including an active ingredient anda compound which is sweet in taste and has a cooling sensation. Such acompound can be selected from the group consisting of mannitol,sorbitol, a mixture of artificial sweetener and menthol, a mixture of asugar and menthol or methyl salicylate.

Another solution to this problem was described in Wehling et al., U.S.Pat. No. 5,178,878 which relates to certain effervescent dosage formscontaining microparticles. The effervescent dosage forms of Wehling etal. provide an effervescent dosage form for direct oral administration.The dosage form is designed to disintegrate rapidly in the mouthreleasing its microparticles as a slurry for ingestion. The dosage formsproduced in accordance with Wehling et al. can be placed in thepatient's mouth and the effervescence contained therein can be activatedon contact by the patient's saliva. The tablet then disintegrates.

Källstrand, et al., U.S. Pat. No. 4,994,260 relates to a pharmaceuticalmixture. The mixture is used for the controlled release of a substance.According to Källstrand, et al., a liquid dosage form is produced usingeither a dry powder or microcapsules which are suspended in a solutionof a release-controlling substance, also referred to as a “sink.”Alternatively, it is possible to encapsulate the release-controllingsubstance, together with a drug, within an encapsulating shell. Therelease-controlling substance may include, inter alia, carbohydrates andcarbohydrate-related compounds, disaccharides, monosaccharides,glycerol, glycol, glycosides of monosaccharides and substances derivedfrom ethylene glycol.

Boder et al., U.S. Pat. No. 5,126,151 relates to an encapsulationmixture. Boder et al. refers to the construction of gums and candies inoral dosage forms. According to Boder et al., microcapsules are producedusing a core material which can be selected from a wide variety ofmaterials including sweeteners, medicaments, drugs, flavoring agents andthe like. These materials can be used, either singularly or incombination, in either a single or multiple part delivery system. Thatis, one or more of these materials may be present within one coatingmatrix or may be separately coated by the matrix and employed alone orin combination in the final product. The resulting formulations are saidto provide a masking of unpleasant tasting drugs such as potassiumchloride and the like, thereby making consumption of the drug moreappealing to the patient. The dosage forms may be prepared in chewabletablet form.

Also of interest may be Schobel et al., U.S. Pat. No. 4,824,681, and Weiet al., U.S. Pat. No. 4,590,075. Encapsulated sweeteners have also beenused to provide an extended release of sweetening in, for example,chewing gum.

Cousin et al., U.S. Pat. No. 5,464,632 discloses a rapidlydisintegratable tablet for oral administration with or without the useof water. The tablet comprises an active substance and a mixture ofexcipients, wherein the active substance is multiparticulate and in theform of coated microcrystals, coated microgranules or uncoatedmicrogranules and wherein the mixture of excipients comprises excipientswhich are responsible for the disintegration. The tablet is intended tobe swallowed and disintegration occurs in less than sixty seconds underthe action of excipients which are responsible for disintegration andwhich are selected from the group consisting of at least onedisintegrating agent and at least one swelling agent.

Cherukuri et al., U.S. Pat. No. 5,587,172 is directed to a comestibleunit which disperses quickly in the mouth and is prepared by subjectinga feedstock comprising a carbohydrate capable of undergoing flash-flowprocessing without use of a solution to provide a shearform matrix;initiating crystallization of the shear/form matrix; forming flowablecompactible micro-particulates by combining an additive with theshearform matrix; and compacting the micro-particulates to form thefinal unit.

Gole et al., U.S. Pat. No. 5,558,880 is concerned with a method forpreparing a solid, porous delivery matrix comprising a porous network ofmatrix material that disperses rapidly in water. The matrix materialcomprises a matrix forming agent and one or more amino acids having fromabout 2 to 12 carbon atoms. The matrix material dispersion is thenlyophilized or subjected to solid-state dissolution to form the solid,porous delivery matrix.

A number of companies have attempted to develop a quick dissolving oraltablet using lyophilization techniques. A number of disadvantages arealso associated with those products. First, water-dissolving compoundsinterfere with the freeze-dry cycle. Second, the product oftentimes hasan unpleasant or bad taste and, third, the lyophilization process itselfis time-consuming and expensive. A lyophilized formulation cannot beused with water soluble active ingredients and is limited to low dosagesof active ingredients. Further, these tablets are very fragile requiringspecial packaging procedures thereby increasing the cost of the finalproduct.

Yet another manufacturer uses effervescence to create a quick dissolvingtablet. Carbon dioxide is generated within the tablet in order to blowthe tablet apart. Once again, the tablets prepared by this process arevery fragile and require special and costly packaging procedures.

Another manufacturer utilizes spun sucrose (“cotton candy”) as a quickdissolving tablet matrix. This is an undesirable technology because ofthe hydroscopic nature of spun sucrose. The resultant tablets are veryfragile and require special packaging.

Yet others have dissolved a preparation of a 3% gelatin bead using aspray-dried process. This is not very efficient in terms of throughput.Animal gelatin and sugars are used to prepare a spray-dried bead whichis mixed with other ingredients and tablets are stamped out using atableting machine.

There remains a need in the art for quick dissolving oral tablets, i.e.,tablets which dissolve and/or disintegrate, without the need for wateror a liquid, in the mouth of a patient. Water or another suitable liquidmay not be convenient or readily available or a patient may experiencedifficulty swallowing. In either situation it would be desirable to usea tablet which can incorporate a large amount of an active ingredient ordrug optionally along with taste-masking excipients and also the releaseof the active ingredient upon contact with the surface of the mouth.

Thus, while the art has long-struggled with developing a more desirableoral pharmaceutical dosage form, there remains a long-felt need for animproved oral dosage form.

An object of the present invention is to develop a relatively quickdissolving or disintegrating oral dosage form that disintegrates in themouth within approximately 60 seconds, preferably less than ten seconds,and has acceptable mouth feel.

A further object of the present invention is to develop a tablet fororal administration with superior taste, convenient administration and ahigh load of active ingredient per unit dose without the need forexpensive packaging procedures.

It is also a primary object of the present invention to prepare afinished product which readily disintegrates or dissolves upon exposureto an aqueous environment. Such a product would be especially useful ina wide variety of applications, including but not limited to thedelivery of pharmaceutical products to a patient, including sterileophthalmic solutions, food application, such as confections including anugget bar or the like, veterinary uses including a chunk of materialintended to be licked by an animal: cosmetics, diagnostics, sanitationof water or water products, carriers for pigments (paint), dispersantsfor dyes, agricultural uses including fertilizers, herbicides and thelike, preparation of a mold or model material and the like.

The mixture of excipients in the rapidly disintegratable tablet providedesirable mouthfeel characteristics and physical properties when thetablet is sintered. Further objects and embodiments of the presentinvention will be made known in the following description of thepreferred embodiments and claims. Though the following description ofthe preferred embodiments focuses on the inclusion of pharmaceuticals asthe active agents, it is to be understood that the desirable propertiesof the inventive methods and dosage forms may be advantageously used inconnection with many different types of active agents.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided a rapidlydisintegratable or quick dissolving product which releases a functionalor active ingredient upon exposure to an aqueous environment. Theproduct comprises at least one functional or active ingredient and amixture of excipients, wherein said excipients provide desiredcharacteristics and physical properties such that when the product issintered or heated, excellent binding characteristics are obtained.

There is also provided a rapidly disintegratable or quick dissolvingproduct. This product is advantageously useful for administration withor without the use of water, said product comprising at least onefunctional or active ingredient and a mixture of excipients, whereinsaid excipients provide desired characteristics and physical propertiessuch that when the product is sintered or heated, excellent bindingcharacteristics are obtained. The product is preferably a tablet whichis intended to disintegrate in the mouth or in the presence of anaqueous environment. The mixture of excipients in the rapidlydisintegratable product preferably provide desirable mouthfeelcharacteristics and physical properties when the tablet is sintered orheated. The sintering or heating is preferably conducted atapproximately 50° C. to 120° C. The mixture can contain at least onebinding agent and the binding agent is preferably polyethylene glycolhaving a molecular weight of approximately 1,000 to 1 million. Therapidly disintegratable product preferably contains a structural agent,preferably gelatin, more preferably fish gelatin.

Applicants have also discovered a process for the preparation of arapidly dissolvable or disintegratable tablet as described above for usewith or without water. Release of the active ingredient simply requiresexposure to an aqueous environment.

The process comprises dissolving at least one bulking agent and at leastone structural agent in a suitable solvent, wherein said solventprovides high porosity upon drying; spray-drying or dispersing saiddissolved mixture to obtain a granulated product which can also bereferred to as a matrix or bead; dry blending at least one bindingagent, and at least one active ingredient with the granulated product toobtain a preformulation product or adding at least one active ingredientto the dissolved components before drying; optionally compressing saidpreformulation to obtain a form such as a tablet; and sintering orheating said preformulation for a sufficient time and temperature toallow the binding agent to change status or melt and allow said bindingagent to resolidify as the temperature is reduced to ambienttemperature. The active ingredient may be added to the solvent, thedissolved components or the dry blended mixture. The binding agent maybe added to the bulking agent, the structural agent, the combinedbulking agent and structural agent or dry blended along with the bead orgranulated product to obtain a preformulation product.

BRIEF DESCRIPTION OF THE DRAWINGS

The FIGURE provides a chart depicting a manufacturing process forpreparing the quick dissolving product of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

The present invention involves the preparation of a quick dissolvingporous structure without lyophilization by creating a porous formulationthereby avoiding many of the disadvantages associated with the priorart. While such a quick dissolving structure would be especiallysuitable for an immediate release formulation for pharmaceuticalapplications, it would also be useful for sustained and controlledrelease applications. In addition, while the invention would beespecially suitable for administering drugs to humans, it is anticipatedthat a product prepared by these teachings would be suitable foradministering drugs to animals and for other uses such as diagnostictest kits, cosmetics, water sanitation, carriers for pigments,agricultural uses, dye dispersions, flavor/sweetening dispersions, ormedicinal agents for dispersion, and the like. Thus a wide number ofuses are envisioned.

The present invention involves the formation of a spray-dried ordispersed granulation product also known as a matrix or bead wherein thebead or granulation product is incorporated in the formation of apreformulation product, optionally compressed, with the addition ofbinding and structural agents wherein said binding agent is activatedwith heat during a sintering or heating step.

One advantage of the present invention for pharmaceutical applicationsis that it can incorporate taste-masking technologies. Further, sincethe active ingredient, e.g., drug, can be added to the formulation in adry state, a wide variety of different types of compounds or activeingredients can be used in the formulation. The active ingredient canalso be placed in a suspension or slurry that can be spray-dried ordispersed independent of solubility. These are significant advantagesassociated with the practice of the present invention.

The finished product of the present invention can be used in a varietyof ways. In particular, the product of the present invention is usefulas a quick disintegrating or quick dissolving pharmaceutical formulationintended for a variety of routes of administration includingintravenous, intramuscular, intraperitoneal, subcutaneous, oral, rectal,vaginal and the like. The oral route of administration would be mostpreferred.

However, the finished product of the present invention could also beused as a means to deliver a nutrient or it can be a diagnostic method,e.g., using monoclonal antibodies. Other uses include a means to deliveran insecticide or a fertilizer. Thus, a wide number of types ofcompounds and materials may be advantageously incorporated into thestructural mass of the present invention. Whatever active ingredient isincorporated into the product of the present invention, it should bepresent in an effective amount per unit volume to achieve the desiredeffect.

The composition of the present invention can also carry a higherpayload, i.e., a larger amount of active ingredient per unit dose whilestill maintaining a small unit size. In the case of pharmaceutical aswell as other applications, the rapidly disintegratable product couldtake the form of a tablet, granules, bar, block, disc, or the like. Forinstance, for pharmaceutical applications, dosage ranges of up to 2,500mg are possible, more likely 1,000 mg. Dosage ranges for the treatmentof humans typically extend from approximately 2 mg to 500 mg, preferably10 mg to 250 mg.

Much higher dosage units are also possible depending on the intended useand the size of the final rapidly disintegratable product. For instance,for water treatment applications, a large block could be placed in alake.

The process of the present invention also advantageously avoids thesignificant time and expense associated with lyophilization.Lyophilization limits the amount of active ingredient to approximately100 mg per unit dose, cannot incorporate active ingredients that exhibithigh water solubility which interfere with the freezing process, andeliminates the use of drug candidates that are associated with anundesirable taste.

The process of the present invention is also advantageous because itdoes not rely on effervescence or carbon dioxide release since theamount of active ingredient is also limited in those processes becausetoo much drug can interfere with the speed of the effervescence, andthereby affect the speed of dissolution/disintegration of the product.

The desirable quick dissolving dosage form of the present invention,when used as an oral pharmaceutical, dissolves or disintegrates rapidlyin the mouth, generally within 3-60 seconds, preferably 10-30 seconds.The dosage form of the present invention also allows the incorporationof a wide range of dosage levels. The solubility or insolubility of theactive ingredient or drug does prohibit the use of the presentmanufacturing process as is the case with the state of the art,particularly lyophilization. The formulation of the present inventioncan achieve individual benefits such as taste masking, preparation ofcontrolled release forms, better stability, better separation, and thelike.

The formulation of the present invention allows the production of arobust dosage form that can be packaged in a wide variety of packagingconfigurations such as bulk bottles, strip, blister and the like.

The process of the present invention provides an oral quick dissolvingdosage form of one or more active ingredients or drugs in which tastemasking can be incorporated, if desirable. The formulation is notlimited to a specific class, category or type of active ingredient andallows for a wide range of such active ingredients or compounds, whichcan be either water soluble or water insoluble.

The quick dissolving dosage forms of the prior art tend to be fragile,cannot incorporate tastemasking, and/or cannot be developed for manydrug agents. The subject technology addresses the limitations of thecurrent technologies and allows the formulation of a much moreacceptable quick dissolving oral dosage form.

In the realm of pharmaceutical use, pharmaceutical dosage forms preparedaccording to the present invention exhibit rapid dissolution uponcontact with physiological solvents, such as water, saliva, orgastrointestinal fluids. Therefore, the present inventive pharmaceuticaldosage forms provide a more rapid dispersion of the pharmaceuticalwithin the body upon ingestion.

Embodiments of the present invention have the following potentialapplications:

Pharmaceutical

1. Dosage forms having mucoadhesive properties.

2. Dosage forms designed to deliver drug at a controlled rate.

3. Dosing units designed to deliver drugs in the eye.

4. Dosing units designed to deliver drugs in vaginal, rectal and otherbody orifices.

5. Solid dosage forms designed to replace liquid formulations.

6. Dry medicated preparations for topical application after resolvation(reconstitution).

7. Preparation of medicated units or sheets for topical application.

8. Preparation of more palatable dosage forms of drugs that exhibitdisagreeable organoleptic properties.

9. Dosage forms for oral delivery of drugs to persons who havedifficulty swallowing tablets or capsules.

10. Immunizing kit.

11. Skin antigen.

Food

1. Preparation of and presentation of dried products composed of foodmaterials.

2. To provide a method for the selective extraction of a material in thesolid form during the drying process.

3. Preparation of confectionery products.

4. Preparation of dosing units for the purpose of modifying properties(e.g., taste, color, etc.) or quality of drinking water.

Veterinary

1. Preparation of dosing units for veterinary use.

2. Preparation of aquarium care and feed products.

Cosmetics

1. Preparation of dry systems for medical and cosmetic use afterresolvation.

Diagnostic

1. Enzyme/cofactors and biochemical carrier systems.

2. In vitro test kit containing reagents.

Sanitary

1. Preparation of dosing units for water purification, for example,chlorine, pH, bacteriostatic and the like.

2. Preparation of fragrance carrier units for personal, household andindustrial use.

3. Aquaculture as nutrients or medicinals.

Other

1. Reconstitutable carrier units for pigmented application for paint andother artistic uses.

2. Agriculture and horticulture products requiring release of activeingredients in the presence of water or rain.

3. Preparation of easily removable mold or model material.

4. Preparation of easily removable space maintenance and/or alignmentaid for construction or manufacturing.

5. Aquaculture for feed for fish, shrimp, and the like.

In the practice of the present invention, a bulking agent is combinedwith a structural agent. Suitable bulking agents for use in the practiceof the present invention include carbohydrates such as sucrose,mannitol, sorbitol, xylose, dextrose, fructose, mannose and the like,calcium carbonate, magnesium carbonate and the like. The amount ofbulking agent useful in the practice of the present invention is anamount sufficient to provide bulk to the overall tablet formed and canrange from approximately 10% to 95% of the entire composition.

The structural agent useful in the practice of the present invention canbe a wide variety of materials. In the area of pharmaceutical sciences,it is preferably agar, gelatin, albumen, chondroitin and the like. Thepreferred structural agent is gelatin. The most preferred gelatin isfish gelatin. Fish gelatin is especially advantageous since it has a lowbloom strength which allows a very high concentration of material on thespray-dried matrix or bead of the present invention. The fish gelatin isalso advantageous because it eventually provides a porous supportstructure that allows the tablet to readily dissolve in the mouth. Thisis one of the preferred embodiments associated with the practice of thepresent invention.

There are other advantages associated with the use of fish gelatin asopposed to using regular gelatin. Regular gelatin can be derived frompigs or cows. Concerns relating to the preparation of kosher products ormad cow disease are eliminated by the use of fish gelatin. In addition,when regular gelatin having a 2 to 3% solids content gets into solution,it cannot be spray-dried because regular gelatin has a bloom strength of100-300 and develops a viscosity that is too high for effective spraydrying. Fish gelatin, on the other hand, has a bloom strength of onlyabout 0-25 so the spray-drying process is thereby made more efficient.

The amount of gelatin useful in the practice of the present invention isan amount sufficient to provide structure or support to the tablet andcan range from approximately 0.1% to 20%, preferably 1 to 3%.

The bulking agent/structural agent mixture is then dissolved in asolvent. Suitable solvents include water, ethyl alcohol, isopropylalcohol, and the like, or a mixture thereof. The preferred solvent is acombination of ethyl alcohol and water in a ratio ranging fromapproximately 1:1 to 1:100. The solvent is present in an amountsufficient to provide the desired porosity to the bead or granulatedproduct upon drying.

The bead or granulated product formed using one or more bulking agentand one or more structural agents ultimately allows a low density tabletto be formed and the granulated product can be readily prepared using aspray-dry or dispersing (including instantizing) procedure. Thus, thestrength of the ultimate product is enhanced by blending the spray-driedor dispersed bead or granulated product with a binding agent along withthe other active ingredients or components. Alternatively, when theactive ingredient or compound is added to the solvent or dissolvedcomponents, a bead or granulated product can be spray-dried or dispersedwhile containing the active ingredient. Therefore, the active ingredientor drug can be introduced into the process in a number of ways.

The bead or granulated product is obtained using any spray-dry ordispersing technique known in the art. The spray-dry technique ispreferred and is intended to produce a quick dissolving or rapidlydisintegratable bead or granulated product. An instantizing techniquemay also be used to obtain the granulated product. The type of spray dryunit and the technique employed varies depending on the unit selectedand can be readily determined by one skilled in the art in order toobtain the product of the present invention.

A binding agent can also be added to the spray-dried or dispersedgranulated product along with the active ingredient. These threecomponents can then be dry blended and optionally compressed, preferablyunder light compression, to form a tablet, bar, block, disc, or thelike. These compressed tablets are then sintered to form a robustultimate tablet. Alternatively, the binding polymer can be introducedalong with the structural agent as well as the bulking agent and/orsolvent. Thus the binding polymer may be introduced into the process ina number of ways.

In a variation of the present process, the active drug may be added tothe spray-dried pretableting formulation in the alternative routedepicted on the right of the Figure. That is, the pharmaceuticallyactive agent or drug could be introduced before the spray-drying step,either along with the solvent or along with the bulking agent andstructural agent in the solvent.

In yet another variation of the process, the binding agent as depictedon the left side of the Figure may be added along with the structuralagent or bulking agent or, alternatively, the binding agent could bedissolved directly into the solvent in any order along with the bulkingagent, structural agent and active ingredient. These variations of theprocess as well as other variations are well-known to those skilled inthe art of pharmaceutical formulations.

Binders include starches, pregelatinized starches, gelatin,polyvinylpyrolidone, methylcellulose, sodium carboxymethylcellulose,ethylcellulose, polyacrylamides, polyvinyloxoazolidone,polyvinylalcohols and the like.

Preferred binding agents useful in the practice of the present inventionincludes polyethylene glycol; C₁₂-Cl₁₈ fatty acid alcohol, preferablystearyl alcohol; polypeptide; and the like. The polypeptide can be anyarrangement of amino acids ranging from approximately 100 to 300,000daltons. Any of the foregoing would be useful in the practice of thepresent invention. The preferred binding agent is polyethylene glycol(PEG) having a molecular weight of approximately 1,000 to 1,000,000. ThePEG, preferably melts at about 50° C. to 90° C., and is intended toresolidify as the temperature of the final sintering or heating stepdecreases. PEG is water soluble and can function both as a binder and asa capillary attractant. The amount of binding polymer useful in thepractice of the present invention is an amount sufficient to melt uponsintering or heating to provide rigidity or strength to the finalproduct and can range from 0.5% to 25% of the weight of the finalproduct.

The preformulated product can optionally be compressed. If it is notcompressed, the granules can be sprinkled on the site of action ordropped into an aqueous environment.

Any technique used for compression would be useful in the practice ofthe present invention, including hand compression or the use oftableting equipment. Such tableting equipment is discussed inRemington's Pharmaceutical Sciences, which is hereby incorporated byreference, in its entirety herein.

The final step in the production of a quick dissolving/disintegratingtablet involves heat treating or sintering the compressed tablet. Bysintering, the inventors mean any process incorporating energy in anyform which results in heat transfer. Energy includes radiation or heat.The process of the present invention uses any form of energy whichresults in an increase in the adhesiveness or agglomerization of thegranules (adhere together) so that the final product is stronger afterthe heat treatment than before. The heat treatment creates intratabletbonds and helps weld the product shape together. The heating can beconducted in an oven, a microwave, convection oven, or the like.Application of mechanical heat in any form is useful in the practice ofthe present invention. Typically, a laboratory oven is set atapproximately 50° C. to 100° C. The heating time depends on the exactcomposition of the mixture but can extend anywhere from 1 minute to 12hours, preferably 3 minutes to 45 minutes. The heating step is intendedto melt the binding agent, such as a solid polyethyene glycol. Moretypically, the sintering is conducted at approximately 90° C. forapproximately 10 minutes. The heat treating or sintering step improvesthe product's strength and durability thereby obviating the need forspecial packaging procedures and allows the product to be jostled duringmanufacture, shipping, and consumer use. Other means ofheating/sintering can be employed and would be known to one familiarwith industrial heating processes. Such heating processes as infraredheat, ultraviolet (UV) and other short wave radiation, microwave heat,radiant heat and industrial equipment designed with such attributescould be equally employed.

Any pharmaceutical agent or active ingredient would be useful in thepractice of the present invention, such ingredients or agents includesystemically distributable pharmaceutical ingredients such as, vitamins,minerals, dietary supplements, as well as nonsystemically distributabledrugs.

Pharmaceutical ingredients may include, without limitation, antacids,analgesics, anti-inflammatory agents, antibiotics, antiviral agents,antiparasitic agents, laxatives, anorexics, antihistamines,antiasthmatics, bronchodilators, laxatives, antiflatulents, antimigraineagents, sedatives, antihyperactives, antihypertensives, tranquilizers,antidepressants, decongestants, beta blockers, H₂-antagonists,antitussives, decongestants, alkaloids, ion exchange resins,anti-cholesterolemics, anti-lipid agents, antiarrhythmics, antipyretics,appetite suppressants, expectorants, anti-anxiety agents, anti-ulceragents, coronary vasodilators, cerebral dilators, peripheralvasodilators, anti-infectious agents, psychotropics, antimanics,neuroleptic agents, central nervous system stimulants, gastrointestinalagents, sedatives, antidiarrheal preparations, anti-anginal drugs,peripheral and brain vasodilators, anti-hypertensive drugs,vasoconstrictors, tranquillizers, antipsychotics, antitumor oranticancer drugs, anticoagulants, antithrombotic drugs, hypnotics,anti-emetics, anti-nausea agents, anti-convulsants, neuromuscular drugs,hyper- and hypoglycemic agents, thyroid and antithyroid preparations,diuretics, antispasmodics, uterine relaxants, antiobesity drugs,anabolic drugs, erythropoietin drugs, hematopoietical agents, uricosuricagents, plant extracts, contrast mediums, cough suppressants, mucolyticsor mucoregulators, antiuricemic drugs, immunodepressant drugs,cholesterol lowering agents, hormones, enzymes, drugs acting on therhythm of the heart, drugs used in the treatment of arterialhypertension, agents, drugs acting on blood coagulability,anti-epileptic agents, muscle relaxants, anti-Parkinson drugs,anorexigenic drugs, vitamins, minerals, dietary supplements, nutritionaladditives and mixtures thereof.

Especially preferred active ingredients contemplated for use in thepresent invention are antacids, H₂-antagonists, and analgesics. Forexample, antacid dosages can be prepared using calcium carbonate aloneor in combination with magnesium hydroxide, and/or aluminum hydroxide.Moreover, antacids can be used in combination with H₂-antagonists.

Analgesics include aspirin, ibuprofen, naproxen, acetaminophen and thelike with or without caffeine.

Other preferred drugs or active ingredients for use in the presentinvention include antidiarrheals such as Immodium AD, antihistamines,antitussives, decongestants, vitamins, and breath fresheners. Alsocontemplated for use herein are anxiolytics such as Xanax,antipsychotics, such as Clozaril and Haldol; non-steroidalanti-inflammatories (NSAID's), such as Voltaren and Lodine;antihistamines such as Seldane, Hismanal, Relafen, and Tavist;antiemetics, such as Kytril and Cesamet; bronchodilators such asVentolin and Proventil; antidepressants, such as Prozac, Zoloft, andPaxil; antimigraines such as linigran, ACE-inhibitors, such as Vasotec,Capoten and Zeetril; anti-alzheimers agents, such as Nicergoline; andCa⁺²-Antagonists such as Procardia, Adalat, and Calan.

The popular H₂-antagonists which are contemplated for use in the presentinvention include cimetidine, ranitidine, famotidine, nizatidine,ebrotidine, mifentidine, roxatidine, pisatidine and aceroxatidine.

The active ingredients most useful in the practice of the presentinvention comprise ibuprofen, nitroglycerin, clarithromycin andazithromycin.

As used in this disclosure, the term vitamin refers to trace organicsubstances that are required in the diet. For the purposes of thepresent invention, the term vitamin(s) include, without limitation,thiamine, riboflavin, nicotinic acid, pantothenic acid, pyroxidine,biotin, folic acid, vitamin B₁₂, lipoic acid, ascorbic acid, vitamin A,vitamin D, vitamin E and vitamin K. Also included within the termvitamin are the coenzymes thereof. Coenzymes include thiaminepyrophosphates (TPP), flavin mononucleotide (FMM), flavin adeninedinucleotide (FAD), nicotinamide adenine dinucleotide (NAD),nicotinamide adenide dinucleotide phosphate (NADP), Coenzyme A (CoA),pyridoxal phosphate, biocytin, tetrahydrofolic acid, coenzyme B₁₂,lipoyllysine, 11-cis-retinal, and 1,25-dihydroxycholecalciferol. Theterm vitamin(s) also includes choline, carnitine, and alpha, beta, andgamma carotenes.

As used in this disclosure, the term mineral refers to inorganicsubstances, metals, and the like required in the human diet. Thus, theterm mineral as used herein includes, without limitation, calcium, iron,zinc, selenium, copper, iodine, magnesium, phosphorus, chromium and thelike, and mixtures thereof.

The term dietary supplement as used herein means a substance which hasan appreciable nutritional effect when administered in small amounts.Dietary supplements include, without limitation, such ingredients as beepollen, bran, wheat germ, kelp, cod liver oil, ginseng, and fish oils,amino acids, proteins and mixtures thereof. As will be appreciated,dietary supplements may incorporate vitamins and minerals.

In general, the amount of pharmaceutical ingredient incorporated in eachtablet may be selected according to known principles of pharmacy. Aneffective amount of pharmaceutical ingredient is specificallycontemplated. By the term effective amount, it is understood that, withrespect to, for example, pharmaceuticals, a pharmaceutically effectiveamount is contemplated. A pharmaceutically effective amount is theamount or quantity of a drug or pharmaceutically active substance whichis sufficient to elicit the required or desired therapeutic response, orin other words, the amount which is sufficient to elicit an appreciablebiological response when administered to a patient. As used withreference to a vitamin or mineral, the term “effective amount” means anamount at least about 10% of the United States Recommended DailyAllowance (“RDA”) of that particular ingredient for a patient. Forexample, if an intended ingredient is vitamin C, then an effectiveamount of vitamin C would include an amount of vitamin C sufficient toprovide 10% or more of the RDA. Typically, where the tablet includes amineral or vitamin, it will incorporate higher amounts, preferably about100% or more of the applicable RDA.

The amount of active agent used can vary widely from a few milligrams to2500 milligrams or more. Of course, the size of the dosage form, therequirements of other ingredients, and the number of, for example,tablets which constitute a single dose will impact the upper limit onthe amount of the pharmaceutically active ingredient which can be used.Generally, however between about 0.1 and 2,500 milligrams of activeagent will be used in accordance with the present invention. Morepreferably between about 1 and about 500 milligrams and most preferablybetween and about 5 and about 250 milligrams of active agent are used.Stated another way, typically between about 0.1 and about 67% of thedosage form may be the active agent, based upon the weight of thefinished dosage form. More preferably, the amount of active agent mayvary from between about 0.6 and about 34% by weight based on the totalweight of the finished dosage form. (A 750 mg tablet was used for thiscalculation.)

Other adjuvants may also be used in forming the quickdissolving/disintegrating tablet of the present invention or indeed, informulating dosage forms as well. Adjuvants include, for example,calcium sulfate NF, dibasic calcium phosphate NF, tribasic calciumsulfate NF, starch, calcium carbonate, microcrystalline cellulose,modified starches, lactose, sucrose and the like, staRx, Avicel,Solka-Floc BW40 Alginic acid, Explotab, AUTOTAB, Guargum, Kaolin,Vecgum, Bentonite, and the like. In general, those may be used in up to20% w/w, but often are used in amounts as low as 3-5% w/w.

In addition to the ingredients in accordance with the present invention,the dosage forms in accordance with the present invention may includeflavors, diluents, colors, binders, fillers, compaction vehicles,non-effervescent disintegrants, and lubricants such as those disclosedin Wehling et al. Fragrances, dyes, sweeteners (both artificial andnatural) and other additives may be present as well.

Flavors incorporated into the composition may be chosen from syntheticflavor oils and flavoring aromatics and/or natural oils, extracts fromplants, leaves, flowers, fruits and so forth, and combinations thereof.These may include cinnamon oils, oil of wintergreen, peppermint oils,clover oil, hay oil, anise oil, eucalyptus, vanilla, citrus oil, such aslemon oil, orange oil, grape and grapefruit oil, fruit essencesincluding apple, peach, pear, strawberry, raspberry, cherry, plum,pineapple, apricot and so forth. Flavors may be present in an amountranging from about 0.5 to 3.0 percent. Lubricants according to thepresent invention may be used in the amount of up to 20 weight percent,and preferably between 0.5 and about 4 weight percent based on the totalcomposition.

Fillers may be used to increase the bulk of the tablet. Some of thecommonly used fillers are calcium sulfate, both di- and tri-basic,starch, calcium carbonate, microcrystalline cellulose, modifiedstarches, lactose, sucrose, mannitol, and sorbitol.

The sweeteners may be chosen from the following non-limiting list:glucose (corn syrup), dextrose, invert sugar, fructose, and mixturesthereof (when not used as a carrier); saccharin and its various saltssuch as the sodium salt; dipeptide sweeteners such as aspartame;dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside);chloro derivatives of sucrose such as sucralose; sugar alcohols such assorbitol, mannitol, sylitol, and the like. Also contemplated arehydrogenated starch hydrolysates and the synthetic sweetener3,6-dihydro-6-methyl- 1,2,3-oxathiazin-4-one-2,2-dioxide, particularlythe potassium salt (acesulfame-K), and sodium and calcium salts thereof.Other sweeteners may also be used.

Lubricants are also useful in tableting formulations. Lubricants caninclude, but are not limited to, the following: magnesium stearate,calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex,polyoxyethyfene monostearate, talc, polyethyleneglycol, sodium benzoate,sodium lauryl sulfate, magnesium lauryl sulfate, light mineral oil andthe like.

Furthermore, dispersion enhancers can optionally be used to enhance thebreakability of the compressed tablet in an aqueous environment. Thedispersants can include starch, alginic acid, polyvinylpyrrolidones,guar gum, kaolin, bentonite, purified wood cellulose, sodium starchglycolate, isoarnorphous silicate, and microcrystalline cellulose ashigh HLB emulsifier surfactants.

Other ingredients can also be used in the present invention includeglidants such as starch, talc, magnesium and calcium stearate, zincstearate, dibasic calcium phosphate, magnesium carbonate, magnesiumoxide, calcium silicate, and silica arogels.

Also, color additives can be used in preparing tablets. Such coloradditives include food, drug and cosmetic colors (FD&C), drug andcosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).These colors or dyes, along with their corresponding lakes, and certainnatural and derived colorants are useful in the practice of the presentinvention. Lakes are dyes absorbed on aluminum hydroxide. Coloringagents may range from between 0.1 to 3.5 weight percent of the totalcomposition.

One skilled in the art of formulations would know when to introduce theforegoing ingredients into the process. The most likely point ofintroduce would be during the dry blending step.

The present invention is a method of making tablets which disintegratequickly in the mouth of a patient. The quick dissolving/disintegratingunits or dosage forms produced in accordance with the present inventiondisintegrate/dissolve nearly instantaneously. However, these tablets arecapable of being manufactured so that they can be handled for packagingand distribution without deterioration of the integrity of the product.

In the past, tablets have been made primarily by compressing feedstockunder extremely high-pressure in order to provide the necessary hardnessfor handling required during packaging and distribution. Consequently,prior art tablets so produced were limited in that their high densityreduces the capability of making them quickly disintegrate in the mouth.High density packing resulting from the high compression hinders thedisintegration and wetting of the interior portion of the tablet.

As a result of the present invention, however, a significant stepforward has been made in the art of preparing tablets which disintegratevery quickly in the mouth. In fact, tablets produced by the presentinvention can preferably disintegrate within seconds.

The foregoing will be better understood with reference to the followingexamples which detail certain procedures for manufacture of tablets inaccordance with the present invention. All references made to theseexamples are for the purposes of illustration. They are not to beconsidered limiting as to the scope and nature of the present invention.

EXAMPLE 1

The goal of this example was to formulate, blend and tablet a quickdissolving tablet containing taste masked chlorpheniramine maleate asthe active ingredient.

Ingredient Amount, g % of Composition Chlorpheniramine Maleate, 10% 1.47 Spray Dried Matrix Bead 14.12 70.6 Polyethylene Glycol, PEG-3350 3.216 Sweeteners 0.6 3.0 Cab-O-Sil 0.14 0.7 Coloring Agents 0.1 0.5 Flavors0.14 0.7 Magnesium Stearate 0.1 0.5

The target tablet weight was approximately 150 mg. The tablet was handcompressed using a ½inch round punch and die set. The mixture wasblended for 10 minutes. The blend was compressed to produce a tablethaving a weight of 150 mg.

Compressed tablets were sintered at 50° C. for 50 minutes in an oven.The tablets disintegrated in a USP Basket-Rack Assembly DisintegrationApparatus in about 10 seconds.

EXAMPLE 2

Chlorphenirarine maleate (CPM) was dissolved in the feed solutiontogether with the other components of the tablet matrix. The solutionwas spray dried. The quick dissolving tablet matrix bead was produced.The bead contained 1.6% CPM.

Ingredient Amount, g % of Composition Matrix with CPM 231 76.0% PEG-335030 9.9% Tri-Calcium Phosphate 36 12.0% Cab-O-Sil 3 1.0%

The target tablet weight was approximately 570 mg. The tablet wascompressed on a Stokes BB-2 tablet press, equipped with nine stations ofa ½inch round flat beveled tooling. The mixture was blended for 3minutes. The blend was compressed to produce a tablet having a weight of570 mg.

Compressed tablets were sintered at 90° C. for 10 minutes in an oven.The tablets disintegrated in a USP Basket-Rack Assembly DisintegrationApparatus in under 15 seconds.

EXAMPLE 3

A quick dissolving formulation was prepared according to the presentinvention.

Spray drying of the tablet matrix was carried out in a spray dryer withan attached active carbon filter for solvent recovery.

The spray-dried matrix was processed as shown in the FIGURE and thetablets prepared sintered at 90° C., as also indicated in the FIGURE.The tablets prepared exhibited a robust nature in that they could bedropped on a table at a height of 2 feet without damage, and yetdisintegrated in the mouth within 30 seconds.

Thus, while there had been described what are presently believed to bethe preferred embodiments of the present invention, those skilled in theart will appreciate that other and further embodiments can be madewithout departing from the spirit of the invention and it is intended toinclude all such further modifications and changes as come within thetrue scope of the claims as set forth herein.

What is claimed is:
 1. A rapidly disintegratable tablet foradministration with or without the use of water, said tablet comprisinga plurality of preformed beads, wherein the beads comprise at least oneactive ingredient and a mixture of excipients, said mixture ofexcipients consisting essentially of at least one bulking agent; atleast one structural agent; at least one suitable solvent; at least onebinding agent; and mixtures and combinations thereof, wherein saidexcipients provide desired characteristics and physical properties;wherein at least one binding agent is mixed with the preformed beads,said binding agent being polyethylene glycol, and when the tablet issintered or heated, excellent tablet binding characteristics areobtained from the binding agent surrounding the preformed beads andbinding them together; and wherein said structural agent is gelatin. 2.The rapidly disintegratable tablet according to claim 1, wherein saidtablet is intended for oral administration.
 3. The rapidlydisintegratable tablet according to claim 2, wherein said tabletdissolves in the presence of water.
 4. The rapidly disintegratabletablet according to claim 3, wherein said mixture of excipients providedesired mouthfeel characteristics and physical properties when thetablet is sintered.
 5. The rapidly disintegratable tablet according toclaim 1, wherein said polyethylene glycol has a molecular weight ofapproximately 1,000 to 1 million daltons.
 6. The rapidly disintegratabletablet according to claim 1, wherein said gelatin is fish gelatin. 7.The rapidly disintegratable tablet according to claim 1, wherein saidsintering or heating is conducted in the range of approximately 50° C.to 120° C.
 8. The rapidly disintegratable tablet according to claim 1,wherein said active substance is selected from the group consisting ofantacids, analgesics, anti-inflammatory agents, antibiotics, antiviralagents, antiparasitic agents, laxatives, anorexics, antihistamines,antiasthmatics, bronchodilators, laxatives, antiflatulents, antimigraineagents, sedatives, antihyperactives, antihypertensives, tranquilizers,antidepressants, decongestants, beta blockers, H₂-antagonists,antitussives, decongestants, alkaloids, ion exchange resins,anti-cholesterolemics, anti-lipid agents, antiarrhythmics, antipyretics,appetite suppressants, expectorants, anti-anxiety agents, anti-ulceragents, coronary vasodilators, cerebral dilators, peripheralvasodilators, anti-infectious agents, psychotropics, antimanics,neuroleptic agents, central nervous system stimulants, gastrointestinalagents, sedatives, antidiarrheal preparations, anti-anginal drugs,peripheral and brain vasodilators, anti-hypertensive drugs,vasoconstrictors, tranquillizers, antipsychotics, antitumor oranticancer drugs, anticoagulants, antithrombotic drugs, hypnotics,anti-emetics, anti-nausea agents, anti-convulsants, neuromuscular drugs,hyper- and hypoglycemic agents, thyroid and antithyroid preparations,diuretics, antispasmodics, uterine relaxants, antiobesity drugs,anabolic drugs, erythropoietin drugs, hematopoietical agents, uricosuricagents, plant extracts, contrast mediums, cough suppressants, mucolyticsor mucoregulators, antiuricemic drugs, immunodepressant drugs,cholesterol lowering agents, hormones, enzymes, drugs acting on therhythm of the heart, drugs used in the treatment of arterialhypertension, anti-migraine agents, drugs acting on blood coagulability,anti-epileptic agents, muscle relaxants, anti-Parkinson drugs,anorexigenic drugs, vitamins, minerals, dietary supplements, nutritionaladditives and mixtures thereof.
 9. The rapidly disintegratable tabletaccording to claim 8, wherein said active substance is selected fromantacids, analgesics, anti-inflammatory agents, coronary vasodilators,peripheral vasodilators, antibiotics, antiviral agents, antianxietydrugs, central nervous system stimulants, antihistamines, hormones,anti-hypertensive agents, bronchodilators, anti-migraine agents, musclerelaxants, anti-epileptic agents, anti-Parkinson drugs, decongestants,diuretics, hypnotic/sedative drugs and expectorants.
 10. The rapidlydisintegratable tablet according to claim 9, wherein said activesubstance is selected from ibuprofen, nitroglycerin, clarithromycin andazithromycin.
 11. A rapidly disintegratable product comprising aplurality of preformed beads, wherein the beads comprise at least oneactive ingredient and a mixture of excipients, said mixture ofexcipients consisting essentially of at least one bulking agent; atleast one structural agent; at least one suitable solvent; at least onebinding agent; and mixtures and combinations thereof, and wherein saidexcipients provide desired characteristics an physical properties;wherein at least one binding agent being polyethylene glycol, and whenthe product is sintered or heated, excellent binding characteristics areobtained from the binding agent surrounding the preformed beads andbinding them together; and wherein said structural agent is gelatin.